Breast cancer is one of the major health problems in the United States affecting approximately one in nine women; it is the most frequent cause of cancer-related death among women. Side progress in therapy appears to have reached a plateau in the mid-1970s, chemoprevention constitutes a plausible alternative approach, i.e. the use of either synthetic or naturally occurring agents to inhibit preneoplastic events before the occurrence of clinically detectable cancers. Epidemiological studies and experiments in laboratory animals indicate the benefits of the micronutrient selenium in cancer chemoprevention. However, the range between chemopreventive and toxic levels of inorganic selenium is narrow. We were the first to report that, in contrast to inorganic selenium compounds, synthetic organoselenium compounds provided better chemopreventive indices, i.e. agents with high chemopreventive efficacy with low toxicity. We will continue our efforts to design less toxic and more effective chemopreventive organoselenium compounds (Specific Aims 1 and 2). On the basis of disposition and metabolism studies of benzyl selenocyanate (BSC) in rats, we concluded that the chemopreventive effects of BSC can not be limited to one form of selenium; the rate of excretion also appears to be a determining factor in chemoprevention. Thus, the metabolism of a recently synthesized BSC derivative, 1,4- phenylenebis(methylene)selenocyanate (p-XSC) will be studied in this program (SpecifiC Aim 3). Animals tolerated p-XSC much better than BSC. Like BSC, p-XSC also inhibits mammary tumors in rats induced by 7,1 2- dimethylbenz[a]anthracene (DMBA). p-XSC inhibits DMBA-DNA adduct formation in the mammary glands which may, in part, account for its chemopreventive action. Preliminary data indicate that dietary p-XSC influences the metabolic profiles of DMBA in the liver and mammary glands. Whether the newly developed organoselenium compounds influence the metabolic profiles of DMBA in the liver, mammary glands, or in both will be examined (Specific Aim 4). The inhibitory effect of p-XSC on DMBA-DNA adduct formation provided a rationale for using this assay for screening other organoselenium compounds as potential chemopreventive agents (Specific Aim 5) in efficacy studies using DMBA (Specific Aim 6). The results of this program combined with those to be obtained in Laboratory Program 3 with respect to pharmacokinetics and effects on Phase I and II enzymes in the liver and in the mammary glands will provide better understanding of the structural requirements for chemoprevention and the mechanism of action of the organoselenium compounds. We believe that the results of this program are prerequisite to provide insights into the feasibility of using an organoselenium compound with a remarkable chemopreventive index in future clinical trials on cancer prevention.